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    Summary
    EudraCT Number:2019-002001-21
    Sponsor's Protocol Code Number:3597
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-08-25
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2019-002001-21
    A.3Full title of the trial
    BETTER-B: BETter TreatmEnts for Refractory Breathlessness. An International, Multicentre, Randomised Controlled Pragmatic Trial of Mirtazapine to alleviate Breathlessness in Palliative and End of Life Care.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    BETTER-B: Better Treatments for Refractory Breathlessness.
    A.3.2Name or abbreviated title of the trial where available
    BETTER-B
    A.4.1Sponsor's protocol code number3597
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN10487976
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity College Dublin
    B.1.3.4CountryIreland
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEuropean Union Horizon 2020 research and innovation programme
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKings College London
    B.5.2Functional name of contact pointProfessor Irene Higginson
    B.5.3 Address:
    B.5.3.1Street AddressCicely Saunders Institute, KCH
    B.5.3.2Town/ cityBessemer Road, Denmark Hill, London
    B.5.3.3Post codeSE5 9PJ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number442078485516
    B.5.5Fax number442078485517
    B.5.6E-mailirene.higginson@kcl.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Mirtazapine KRKA 15mg Film-Coated Tablets
    D.2.1.1.2Name of the Marketing Authorisation holderKRKA Sverige AB
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMirtazapine KRKA 15mg Film-Coated Tablets
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMirtazapine
    D.3.9.1CAS number 61337-67-5
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Refractory breathlessness in patients diagnosed with chronic obstructive pulmonary disease (COPD) or interstitial lung disease (ILD).
    E.1.1.1Medical condition in easily understood language
    Breathlessness that continues despite optimal management of the underlying causes and current symptom relief measures, in patients suffering from lung disease.
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine whether mirtazapine is an effective treatment for the reduction of self-reported worst breathlessness over the past 24 hours measured at day 56 post start of treatment compared to placebo in patients with COPD (Chronic Obstructive Pulmonary Disease) or ILD (Interstitial Lung Disease) in palliative and end of life care.
    E.2.2Secondary objectives of the trial
    To assess the effectiveness of mirtazapine, compared to placebo, over time at days 7,14, 28, 56 & 180

    To evaluate safety, toxicity and tolerability of mirtazapine

    To identify which patient characteristics are most associated with benefit from mirtazapine, specifically assessing the impact of age: gender; functional status; aetiology; and baseline intensity of: breathlessness and its characteristics; anxiety; depression; and concomitant opioid administration

    To assess the cost-effectiveness of mirtazapine treatment from a societal perspective (i.e. including formal and informal care received), when compared with best standard care

    To demonstrate the feasibility of delivering mirtazapine treatment across the different European countries in terms of acceptability of the offered treatment and compliance with treatment

    To evaluate the impact of patients receiving mirtazapine on caregivers, in particular primary caregiver reports of their time in hours, burdens and experiences
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The BETTER-B sub-study is the Caregiver sub-study. The aim of this sub study is to assess the caregiver burden and the experience of the participants caregivers and close family members.
    E.3Principal inclusion criteria
    1.Aged ≥ 18 years old
    2.Diagnosed with:
    •Chronic obstructive pulmonary disease (COPD), and/or
    •Interstitial lung disease (ILD), including chronic fibrotic lung disease following SARS-CoV-2 infection
    3.Breathlessness severity: Modified MRC (mMRC) breathlessness scale of:
    •Grade 3 (I stop for breath after walking about 100 yards or after a few minutes on level ground) or
    •Grade 4 (I am too breathless to leave the house, or I am breathless when dressing or undressing)
    4.On optimal treatment of the underlying condition in the opinion of the identifying clinician (see section 9.3.3 of the protocol for guidance)
    5.Management of the underlying condition unchanged for the previous 2 weeks
    6.Reversible causes of breathlessness optimally treated in the opinion of the identifying clinician
    7.If female, must be (as documented in patient notes):
    a)postmenopausal (no menses for 12 months without an alternative medical cause), or
    b)surgically sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy), or
    c)using acceptable contraception (which must be continued for 7 days after the last dose of IMP)
    8.Able to complete questionnaires and trial assessments
    9.Able to provide written informed consent


    Caregiver eligibility:
    Caregivers will be identified by an included patient participant as the person closest to them, providing the patient participant is willing for them to be approached.

    Caregivers must meet all of the following criteria to be eligible:
    1.Identified by an included patient as the person closest to them
    2.Aged ≥18 years old
    3.Able to complete questionnaires and assessments
    4.Able to provide written informed consent
    E.4Principal exclusion criteria
    1.Existing antidepressant use , or other serotonergic active substances (e.g. linezolid, St John’s wort)
    2.Known contraindication to mirtazapine
    3.Hypersensitivity to the active substance or to any of the components of mirtazapine or placebo (e.g. lactose intolerance)
    4.Australia modified Karnofsky Performance Scale ≤40
    5.Pregnant or breast-feeding women. For women of childbearing potential (those not post-menopausal or surgically sterile) this must be confirmed by a pregnancy test (urine) within 7 days prior to randomisation
    6.Patients with known cardiovascular disease or acute cardiac events within 3 months prior to randomisation (e.g. myocardial infarction, unstable angina pectoris, or significant cardiac conduction disturbance)
    7.Patients with jaundice or known hepatic impairment in the opinion of the identifying clinician (e.g. bilirubin >25micromol/L, and AST and ALT >2 times upper limit of normal )
    8.Patients with known renal impairment in the opinion of the identifying clinician (e.g. creatinine >132micromol/L and eGFR <30mL/min/1.73m2 x)
    9.Patients with uncontrolled blood pressure in the opinion of the identifying clinician
    10.Patients with uncontrolled diabetes mellitus in the opinion of the identifying clinician
    11.Patients with uncontrolled seizures, epilepsy or organic brain syndrome in the opinion of the identifying clinician
    12.Patients with severe depression or suicidal thoughts in the opinion of the identifying clinician
    13.Patients with a history of psychotic illness (schizophrenia, or other psychotic disturbances) in the opinion of the identifying clinician
    14.Patients with bipolar disorder, or a history of mania or hypomania in the opinion of the identifying clinician
    15.Patients currently enrolled in another interventional trial
    16.Patients with known congenital QT prolongation or family history for QT prolongation.
    17.Use of medicines that cause QT prolongation such as macrolides and typical antipsychotics (unless required in low-dose to relieve nausea, e.g. haloperidol ≤5mg/24h, levomepromazine ≤25mg/24h).
    18.Patients with a known history of suicide-related events

    E.5 End points
    E.5.1Primary end point(s)
    The primary objective is to determine whether mirtazapine is an effective treatment for the reduction of self-reported worst breathlessness over the past 24 hours measured at day 56 post start of treatment compared to placebo in patients with COPD or ILD in palliative and end of life care. The primary endpoint is worst breathlessness over the last 24 hours at day 56 post start of treatment as assessed by numerical rating scale (NRS, 0=no breathlessness to 10=worst possible breathlessness). Day 56 post start of treatment was chosen to allow sufficient time for the intervention to have an effect, it is a timescale which will be useful in palliative and end of life care and we can collect the primary outcome without too much attrition.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary outcome will be evaluated when all participants have reached day 56 post start of treatment.
    E.5.2Secondary end point(s)
    •Worst breathlessness over the last 24 hours as assessed by NRS (0=no breathlessness to 10=worst possible breathlessness) at days 7, 14, 28 and 180 post start of treatment [objective 1a];

    •Average breathlessness over the last 24 hours assessed by NRS (0=no breathlessness to 10=worst possible breathlessness) at days 7, 14, 28, 56 and 180 post start of treatment [objective 1a];

    •Number and duration of episodes of breathlessness over the last 24 hours [objective 1b];

    •Physical and emotional aspects of breathlessness (Dyspnoea, fatigue, emotional function, mastery) as assessed by the Chronic Respiratory Questionnaire (CRQ) at days 14, 28, 56 and 180 post start of treatment [objective 1c];

    •Physical symptoms as assessed by the Integrated Palliative care Outcome Scale (IPOS) at days 14, 28, 56 and 180 post start of treatment [objective 1c];

    •Quality of Life (QoL) as assessed by the EQ-5D-5L and associated VAS at days 14, 28, 56, 180 post start of treatment and Australia-modified Karnofsky Performance Scale (AKPS) at days 14, 28, 56 and 180 post start of treatment [objective 1c];

    •Anxiety and depression as assessed by the Hospital Anxiety and Depression Scale (HADS) at days 28, 56 and 180 post start of treatment [objective 1d];

    •Perceived self-efficacy as measured by the Generalized Self-Efficacy Scale (GSES) at day 56 post start of treatment [objective 1d];

    •The consumption of opioids as measured by opioid medication usage at days 7, 14, 28, 56 and 180 post start of treatment [objective 1e];

    •Healthcare services received, including out of hours care, number of emergency hospital attendances and admissions within 28 and 56 days post start of treatment and in the 3 month period prior to day 180 post start of treatment as measured by the Client Services Receipt Inventory (CSRI) [objective 1f];

    •Safety as assessed by the occurrence of:
    oSAEs, SARs and SUSARs coded according to mild, moderate or severe as reported at days 7, 14, 28 and 56 post start of treatment [objective 2];
    oDeaths by day 56 and day 180 post start of treatment [objective 2];

    •Toxicity as assessed by adverse reactions (ARs) coded according to mild, moderate or severe as reported at days 7, 14, 28 and 56 post start of treatment [objective 2];

    •Tolerability as assessed by the proportion of patients not withdrawing due to adverse reactions [objective 2];

    •Baseline demographics and characteristics will be measured to enable prognostic evaluation of those factors most associated with benefit from mirtazapine (benefit as measured by worst breathlessness over the last 24 hours at day 56 post start of treatment. Specifically assessing:
    oage,
    ogender,
    ofunctional status (as measured by actual functioning using AKPS, mobility using EQ-5D-5L, and ‘poor mobility’ using IPOS), aetiology (COPD / ILD),
    obaseline intensity of breathlessness (as measured by worst breathlessness over the last 24 hours at baseline),
    oanxiety and depression (as measured by HADS),
    oconcomitant opioid administration [objective 3];

    •Formal and informal care use over the previous period as measured by the Client Services Receipt Inventory (CSRI) at days 28, 56 and 180 post start of treatment, to examine hours of care and (using country specific unit costs) costs of services [objective 4];

    •Acceptability of the offered treatment as assessed by the recruitment conversion rate, the number of people withdrawing from treatment, and the number of participants who request mirtazapine from their doctor/clinician after 56 days post start of treatment [objective 5];

    •Treatment compliance as measured by the:
    oproportion and type of dropouts over 56 days post start of treatment,
    oproportion of tablets taken over 56 days post start of treatment,
    oproportion of participants who escalate dose at days 14 and 28 post start of treatment,
    ooff trial treatment compliance to 180 days post start of treatment [objective 5];

    •Caregiver’s perceived impact on the participant and themselves [objective 6] as measured by:
    oWorst and average rating of the participant’s breathlessness over the last 24 hours as assessed by NRS (0=no breathlessness to 10=worst possible breathlessness) at days 28, 56 and 180 post start of treatment;
    oCaregiver assessment of the participant’s number and duration of episodes of breathlessness over the last 24 hours;
    oInformal care hours as measured by the Client Services Receipt Inventory (CSRI) at days 28, 56 and 180 post start of treatment;
    oCaregiver self-reported burden as measured by the Zarit Burden inventory at days 28, 56 and 180 post start of treatment;
    oCaregiver self-reported experiences of caregiving as measured by the Positive Aspects of Caregiving scale (PAC) at days 28, 56 and 180 post start of treatment;
    oCaregiver perspectives on participants’ situation as measured by the Integrated Palliative care outcome scale (IPOS) at days 28, 56 and 180 post start of treatment.
    oCaregiver overall health and we
    E.5.2.1Timepoint(s) of evaluation of this end point
    All secondary endpoint will de evaluated when all participants have been followed up to completion i.e. 180 days post randomisation.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of trial is defined as the date of the final data download for final analysis.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 162
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 162
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 219
    F.4.2.2In the whole clinical trial 324
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    If participants believe they have had a benefit from the trial treatment, they may wish to take mirtazapine off-trial. Participants are advised that they may approach their GPs following trial completion for off-trial prescribing of mirtazapine.

    The trial stipulates that participants should have dose tapered back to 15mg or completed dose tapering before approaching their GP for a prescription.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-10-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-11-18
    P. End of Trial
    P.End of Trial StatusOngoing
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